Our long-term goal is to understand the pathobiology associated with viral hepatitis and liver cancer. Hepatitis B virus (HBV) is the 4th most common infectious agent in humans. Chronic infection with HBV is tightly associated with the development of liver cancer. Although both hot immune and viral factors are believed to contribute to the establishment of chronic infection, the mechanism of HBV chronic infection remains to be fully explored. Defective interfering (DI) particles have been found in many RNA and DNA viruses of bacteria, plants, and animals, and are known to be associated with persistent infection in tissue culture. However, the existence of DI particles has not yet been demonstrated in human natural infections since their first discovery in influenza virus by von Magnus (1947) in the laboratory setting. Using a new approach, we provided the first experimental evidence for the existence of DI-like viruses in human chronic HBV carriers. Functional characterization of these naturally-occurring "core intentional deletion variants" (CID) of HBV reveals all of the characteristic features of DI particles. In this application, we propose to study the biological significance of CID variants in patients and woodchuck animal model. We will investigate the phenomenon of fluctuating titers of HBV CID variants in human patients. In addition, we propose to investigate if woodchuck hepatitis virus (WHV) core internal deletion variants, which we have found recently (manuscript submitted) also behave like DI particles in tissue culture. Finally, we will continue our studies of the mechanism of defective interference of HBV CID variants by both genetic and biochemical approaches. A "repressor-like model" versus a "preferential replication" model will be distinguished. Successful completion of this work will have important implications for chronic viral hepatitis which leads to the development of highly malignant liver cancer.